Can a small A-kinase anchoring protein have a big role in cancer?
Profiling student research
If you don't know Ekaterina Perets personally, you surely remember the article she wrote on the festival Rosh ha Shana in Insights. Ekaterina, an Israeli PhD student in the lab of Enno Klußmann, recently saw an email inviting scientists to one of the "open-door writing labs" hosted every couple of weeks by the Communications Department. That's when we invite researchers to come by for individual help with communications projects, on a walk-in basis. In walked Ekaterina, who said she was facing two daunting writing projects: a paper and her thesis.
That visit led to her article in this issue of Insights: a summary of her PhD project in Enno’s lab, written with an audience of students and non-specialists in mind.
Insights hereby invites other students to follow her lead. If you're working on something that you think might interest readers of Insights on campus and beyond, and would like to share it while getting feedback on your writing, contact the editors. Or watch your email for the date of the next writing lab and drop by.
Can a small A-kinase anchoring protein have a big role in cancer? A report from the lab bench
The ability of cancer cells to detach themselves from an initial tumor site, migrate and invade other tissues signifies the first step of metastasis, which is often the fatal step in cancer progression. Cells must achieve a complex reorganization of multiple intracellular processes to initiate this process. Collectively, the steps in this transition are called EMT (Epithelial-Mesenchymal Transition), and a central goal of modern cancer research is to gain further insights into the induction and regulation of EMT.
The breaking of extracellular bonds between metastasizing cancer cells and an initial tumor is usually a good predictor of poor prognosis. In some cases this type of breakaway is reflected by uncoupling of extracellular protein-protein interactions that normally bind the cell to the extracellular matrix. However, intracellular protein-protein binding is a much more general phenomenon that is crucial to every aspect of cellular life, which therefore requires proper regulation. Many proteins have different functions depending on their location inside the cell and change functions when they attach themselves to different cellular structures. These kinds of attachments are often facilitated by scaffolding proteins, which can bind to membranes or other structural elements in specific cell compartments.
One example of a location-dependent protein that has been found to malfunction in various tumors is a signaling molecule called GSK3β. When GSK3β is in the cytoplasm of the cell or in the nucleus, its main role is to transmit information important for cells’ development as well as for the regulation of EMT. In these locations, GSK3β mainly participates in an information circuit called the Wnt signaling pathway. However, when GSK3β in located within cellular structures called mitochondria, it transmits information that helps determine whether abnormal cells survive or die. In order to grow, survive and metastasize cancer cells must disrupt signals passed along by GSK3β to other proteins further down the cellular chain of command. Therefore, ensuring that GSK3β can function properly is crucial in cancer prevention and treatment.
GSK3β’s activity depends on both its location and physical interactions with other proteins, two themes which are connected. Under normal conditions, GSK3β remains active and can be inhibited by a phosphate group placed on it by proteins called kinases, including Protein Kinase A (PKA). That requires bringing PKA close enough to GSK3β to transfer a phosphate group to it, a meeting that is likely mediated by scaffolding proteins such as GSK3β interacting protein (GSKIP).
GSKIP belongs to the family of A-kinase anchoring proteins (AKAPs). AKAPs share a common feature: the ability to bind PKA and transport it to a particular location inside the cell. Thus the interaction with GSKIP directs not only GSK3b but also PKA to defined cellular locations. PKA itself is known to have many roles in tumorigenesis. Within the complex containing GSKIP, PKA and GSK3b, PKA can inhibit GSK3β by transfer of a phosphate onto it. This suggests a possible role for GSKIP in tumorigenesis, but so far, its functions have been unclear.
We silenced the GSKIP gene in a cancer cell model used by our lab and discovered that the molecule contributes to specific processes involved in metastasis and other tumorigenic events. For the details you’ll have to wait for the paper. For now we can say that the silencing of GSKIP affects the behavior of proteins that play crucial roles in signaling, EMT, and cellular metabolism.
In 1929 Otto Warburg discovered that metabolic reprogramming is a hallmark of cancer, noting that rapidly growing cancer cells rely on different methods of energy production than healthy, slow-growing cells. He stated that cancer cells produce most of their energy through a process called anaerobic glycolysis, whereas healthy cells prefer the more highly efficient means of energy production offered by oxidative phosphorylation (OXPHOS), which takes place in the mitochondria. This switch is important because anaerobic glycolysis is much faster. While Warburg thought that all cancer cells switch to high-rate glycolysis, recent studies have shown that this is true only for cancer cells undergoing rapid growth and cell divisions. Other tumor cells – such as those that metastasize – prefer OXPHOS. When you read the paper you’ll see how we demonstrated GSKIP’s effects on metabolism and how we interpret them in terms of the dysregulation of metabolism and EMT.
A lot of questions remain: proteins directly targeted by GSKIP have yet to be found. The project raises a “chicken-or-egg” question: which is affected by GSKIP first – EMT or metabolism? Our approach should contribute to elucidating mechanisms that underlie the kinds of changes in these processes that are observed in tumorigenesis. And it hints that GSKIP might make a therapeutic target. This would be useful because GSKIP and other AKAPs have features that might permit fine-tuning their effects. It might be possible to alter the behavior of GSK3β in one location, where its regulatory activities contribute to disease, without affecting processes in other locations that are required for health.
Read more information about Enno Klußmann's group here.
